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Currently, I'm cold most of the time, always wear a scarf, and even wear a girdle around my waist to try to stay warm. I surely cannot subject my 5'9" 105lb body to cold as described in this thread w/o snuffing out my QOL and ability to be productive. Interestingly, for the first 10 yrs of my CR I surfed in the very cold Pacific Ocean for an hour a day. I seem to be much healthier now for the past two years without the cold water exposure (it's complicated--I'm just saying). I do eat lots of curcumin. Great work on the research. I've always been intrigued and wondered about human CR and cold exposure, too.

Edited February 23, 2016 by Kenton

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Holy cow Kenton! That's a BMI of 15.5. That's pretty darn low. Be careful. I can certainly see why cold exposure (or cold water surfing) is not an appealing or viable option for you, at that level of CR. I just wonder if being that low is wise. But if you're feeling good (physically & psychologically), more power to you!

P.S. Do you plan to be at the CR Conference? I'd love to finally meet you in person!

--Dean

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Dean, I think you could do a TED talk called "The unifying theory of longevity!" Haha. To add to your list, "women have more BAT and live longer" and "lean people have better BAT activation than overweight people, and live longer".

Regarding the last 2 posts, I suspect that extreme low BMIs will end up being counter productive and life shortening. Research has shown that brown fat activation is muted or non-existent in humans with extremely low BMIs. Then you have the bone and muscle loss problems, and the studies of centenarians which suggest very low bmi does not result in longevity for humans.

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You are right about women and naturally lean people having more BAT, and overweight/obese people having less. But in this post we saw that leanness as a sole result of severe calorie deficit (i.e anorexia) did not lead to BAT expression. So it requires more than just "getting lean" to increase one's BAT. Unfortunately being a woman or being naturally lean are not modifiable lifestyle factors that one can engage in to increase BAT. Another non-modifiable factor that is (inversely) associated with increased BAT expression is age. This study [1] measured the BAT levels in 4000 Chinese men and women. In addition to finding more BAT in women than men, and more BAT in thin than overweight/obese people, it found that BAT was quite rare in older individuals. Here is a graph of the percent of people with detectable BAT as a function of age (left) and BMI (right):

As you can see, it's really uncommon for adults over 50 or with a BMI > 25 to express BAT, at least in among the Chinese subjects in this study. They also found that people with detectable BAT were much less likely to suffer from markers for metabolic syndrome - visceral fat accumulation, high triglycerides & cholesterol and high fasting glucose, but it's not clear whether extra BAT expression causes improvements in metabolic syndrome risk factors, either directly (e.g. by burning triglycerides) or indirectly (e.g. by preventing obesity via increased calorie expenditure), or is simply correlated with reduced risk factors (i.e. increased BAT and improved risk factors both resulting from reduced obesity).

Finally, this graph was interesting, in that it demonstrates that presumably unintentional cold exposure is associated with increased BAT expression. It compares the percent of subjects with detectable BAT as a function of outdoor temperature on the day of the scan - a proxy for the season (winter vs. summer) in Shanghai where the study was conducted. Note the 4000 subjects were scanned over the course of an entire year, providing a good distribution of ambient temperatures:

As you can see, if it is was winter / cool outside (< 68 °F) people were much more likely to express BAT. And it wasn't that subjects were simply colder during the scan when it was done in the winter, since they were all kept at thermoneutral conditions (75 °F) for at least an hour prior to and during the scan. More evidence that folks who live in warm climates might be at a disadvantage relative to BAT expression.

Speaking of climate - there is also evidence that the climate of one's ancestors influences BAT expression. Study [2] compared BAT levels in "Dutch nationals with south Asian ancestry and matched Caucasian participants". They found that caucasians had 50% more BAT than people with south asian ancestors, despite all of them living in the same (northern) city in the Netherlands. Picking up on this observation, the same group of researchers suggest in [3] that the unusual high rate of cardiovascular disease among south asian populations may be a result of lower BAT expression:

A contributing factor that may underlie the development of this disadvantageousmetabolic phenotype is the presence of a lower amount of brown adipose tissue(BAT) in South Asian subjects, resulting in lower energy expenditure and lowerlipid oxidation and glucose uptake. As it has been established that the increasedprevalence of classical risk factors in South Asians cannot fully explain theirincreased risk for CVD, other non-classical risk factors must underlie thisresidual risk.

More evidence that one's ancestry may play a significant role in BAT expression comes from this oldie but goodie from 1957 [4]. Researchers subjected healthy men of Caucasian, Inuit or African descent to an air temperature of 17°C. They found the Inuits had the highest baseline thermogenesis and that cold exposure resulted in twice the increase in thermogenesis in the Caucasian and Inuit men relative to the men with African ancestry:

After 55 minutes of exposure, both the Caucasian and Eskimo subjects demonstrated an average rise in metabolism of 22 Cal/hr/m2 above control levels of 40 and 55 Cal/hr/m2, respectively. Negro subjects showed an increase in body heat production of only 10 Cal/hr/m2 after 85 minutes in the cold room. Although the absolute levels of heat production differed for the Eskimo and Caucasian groups, these subjects responded in a similar fashion to the standard cold stress.

I can't get the full text of [4] to see whether the men were all from the same region, to eliminate possible effects of cold acclimation between the three sets of subjects. But the results generally seem to support the notion that one's genetic heritage may influence BAT expression.

While several of the factors discussed above (like gender, age and ethnicity) are non-modifiable, I think you are right that it's worth listing them. Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT expression:

Cold exposure - by far the best BAT inducer/activator

Metformin

Green tea

Caffeine

Capsaicin

Curcumin

Exercise

Low protein diet

Avoid obesity/overweight

[being naturally thin - high metabolic rate]

[being younger]

[being female]

[Ethnicity - having cold-climate ancestors]

I think you could do a TED talk called "The unifying theory of longevity!" Haha.

It is striking how many of these BAT-inducers are known (or thought) to be associated with increased health & longevity. Of course correlation is not causation, but the fact that all of these disparate interventions/characteristics result in increased BAT and better health/longevity is certainly suggestive of a causal chain with BAT in the middle, mediating the benefits.

dysfunction are higher compared with Caucasians. We conclude that a potential

novel therapy to lower CVD risk in the South Asian population is to enhance BAT

volume or its activity in order to diminish classical risk factors. Furthermore,

anti-inflammatory therapy may lower non-classical risk factors in this population

and the combination of both strategies may be especially effective.

PMID: 25955567

--------------

[4] J Appl Physiol. 1958 Jan;12(1):9-12.

Racial variations to a standardized cold stress.

ADAMS T, COVINO BG.

Abstract

Healthy, male, Negro, Caucasian and Eskimo subjects were subjected nude to an air temperature of 17°C. Rectal, average skin and extremity temperatures, body metabolism, sweating rates and electromyograms were obtained at 5-minute intervals throughout the duplicate exposure periods for each individual. After 55 minutes of exposure, both the Caucasian and Eskimo subjects demonstrated an average rise in metabolism of 22 Cal/hr/m2 above control levels of 40 and 55 Cal/hr/m2, respectively. Negro subjects showed an increase in body heat production of only 10 Cal/hr/m2 after 85 minutes in the cold room. Although the absolute levels of heat production differed for the Eskimo and Caucasian groups, these subjects responded in a similar fashion to the standard cold stress.

Submitted on July 24, 1957

PMID: 13502249

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In my previous post, I said it was unclear from the study of 4000 Chinese people whether the association between BAT and better cardiovascular risk factors was a causal relationship, or just a correlation. This study [1] from last month suggests that the relationship may be causal. It found:

BAT activity negatively correlated with arterial inflammation (r=-0.178, p<0.01), a relationship that persisted after correcting for age and BMI (r=-0.147, p<0.01). Using either high sensitivity or high accuracy thresholds (from receiver operating curve analyses) to define elevated BAT, high BAT was associated with a reduced risk of CVD events (P = 0.048) even after correcting for age (P = 0.037).

So arterial inflammation and cardiovascular events were lower in people who had higher amounts of BAT, independent of age and BMI. The 'survival' curves (actually curves for 'time free from CVD events') during the 4.5 years of follow-up for people with high BAT activity (green) and low BAT activity (blue), for two different BAT-activity thresholds, are shown below:

Remarkably, the graph on the right shows that people with high BAT activity had zero CVD events vs. 30 CVD events (~10% of population) in the low-BAT group, during the 4.5 years of followup, the authors said:

Further, no [CVD] events were observed in subjects with high BAT activity,

raising the possibility that BAT could have an important role in vasoprotection.

In short, these results suggests that BAT isn't just associated with reduced risk of cardiovascular disease, via its impact on body weight / adiposity. Instead having increased BAT activity may cause a reduction in CVD risk, independent of age and body weight.

Obesity has become a major public health problem. Given the current increase in life expectancy, the prevalence of obesity also raises steadily among older age groups. The increase in life expectancy is often accompanied with additional years of susceptibility to chronic ill health associated with obesity in the elderly. Both obesity and ageing are conditions leading to serious health problems and increased risk for disease and death. Ageing is associated with an increase in abdominal obesity, a major contributor to insulin resistance and the metabolic syndrome. Obesity in the elderly is thus a serious concern and comprehension of the key mechanisms of ageing and age-related diseases has become a necessary matter. Here, we aimed to identify similarities underlying mechanisms related to both obesity and ageing. We bring together evidence that age-related changes in body fat distribution and metabolism might be key factors of a vicious cycle that can accelerate the ageing process and onset of age-related diseases.

Caloric restriction (CR) has been shown to prevent the age-associated loss of mitochondrial function and biogenesis in several tissues such as liver, heart, and skeletal muscle. However, little is known about the effects of CR on a tissue in which the mitochondria have no adenosine triphosphate (ATP)-producing purpose but show a high degree of uncoupling, namely brown adipose tissue (BAT). Hence, the aim of the present study was to analyze the effect of long-term CR on BAT mitochondrial function and biogenesis. BAT mitochondria obtained from 24-month-old male and female rats previously subjected to 40% CR for 12 months were compared with mitochondria from old (24 months) and young (6 months) ad libitum fed rats. Old restricted rats compared to old ad libitum fed ones showed a reduction in BAT size with respect to fat content and adipocyte number. Mitochondrial DNA content in BAT increased with age and even more so in restricted rats, indicating a summative effect of age and CR on mitochondrial proliferation. CR induced resistance to lose total and mitochondrial protein, COX activity, and uncoupling capacity with advancing age, in relation with a lower decrease of mitochondrial transcription factor A (TFAM). In summary, our results demonstrate CR prevents the age-associated decline in mitochondrial function in BAT, probably in relation with a lower impairment of mitochondrial biogenesis.

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Thanks for the new review article (PMID: 26846415). It is a pretty good overview of obesity & aging, and as you said has a pretty long section on brown adipose tissue. Nothing particularly new though.

But the other one you pointed to, Valle et al (PMID 18593277), which was reference in the review, turns out to be much more interesting than the review itself. It looked at BAT mass and BAT activity in old rats fed either AL or 40% CRed. It is important to note that all the rats were housed at 71 °F for the entire experiment, a temperature well below thermal neutrality.

What they found was that BAT mass was reduced in old CRed rats relative to AL-fed old rats, even after adjusting for body weight. Here is the table, with the relevant cells highlighted:

As you can see, the old CRed rats had about 60% less total brown adipose tissue and about 30% less BAT as a percentage of body weight relative to old AL-fed rats. So in contrast with all those other, health-promoting interventions I've listed that increase the amount of BAT, CR appears to decrease the amount of BAT tissue. This is consistent with the results seen in anorexic women (PMID 23393181; discussed here), none of whom exhibited detectable levels of BAT, even after refeeding to raise their BMI to 19.

But here is where it gets most interesting. In the old CR rats the number of mitochondria in BAT cells, and the amount of mitochondrial DNA in BAT cells, was dramatically increased relative to the old AL-fed rats. This resulted in much greater expression of the uncoupling protein UCP1 (with promotes clean burning of fat to produce heat rather than to generate useful energy via ATP) in each BAT cell of CR rats relative to the AL rats. Here is a graph of UCP1 protein in the mitochondria of BAT cells of young (Y), old AL-fed (O) and old calorie restricted (OR) rats.

As you can see, CR dramatically increased the amount of uncoupling protein-1 in the mitochondria of BAT cells in both male and female rats. So the CRed rats had both more mitochondria in their BAT cells, and each of the mitochondria had more UPC1. So despite having dramatically less BAT, the BAT the CRed rats did have was more metabolically active, preserving the ability of the CRed rats to generate heat via BAT thermogenesis. Here is the researchers commentary on this result from the discussion section:

In broad terms, we observed that old restricted animals compared to old ad libitum fed ones have a reduced BAT size, even normalized per body weight, which probably is due to a lower fat content and adipocyte number in the tissue. ... As happens in liver or skeletal muscle, CR was also shown to promote mitochondrial biogenesis in BAT. On the whole, this conservation of BAT thermogenic capacity may confer several advantages, such as a higher ability to respond to cold exposure or to control body weight when food supply is restored, and, therefore, be part of the rejuvenation mechanisms underlying the life-span extension induced by CR.

I find this study really interesting. Here's why. BAT thermogenesis is very metabolically expensive. Just a few ounces of BAT in people can burn hundreds of calories per day. If it were neutral (to say nothing of deleterious) with respect to health / longevity, you would expect nature/evolution to say "the hell with it" and eliminate it as part of the "hunkering down" program that kicks in when calories are scarce. After all, it jettisons nearly all of its white adipose tissue, which is much less metabolically expensive to maintain than BAT. But in rats at least, this isn't the case. Instead, some brown fat, and nearly all BAT thermogenic capacity, is maintained even when calories are severely limited. This suggests to both to me and apparently the authors, as indicated in the bold section of the quote above, that BAT thermogenesis may be part of the "rejuvenation mechanisms" underlying the lifespan benefits of CR.

But several caveats are required in trying to generalize these rodent results to humans. First and most obviously, these were rats and not humans. Among the many differences, rodents express BAT much more readily than adult humans do, likely as a result of their higher need for thermogenesis due to their higher surface-to-volume ratio, and due to the fact that they spend much of their lives below their thermally neutral temperature. Plus, all the rats in this experiment were kept at a temperature well below thermal neutrality. If they were kept in warmer, thermally-neutral conditions, they may have jettisoned what little BAT they retained, and hence their thermogenic capacity, as was seen in this study [1]. And as we saw in this study (PMID 25362635; discussed here), BAT-thermogenesis (resulting from cold exposure) may indeed be necessary for the longevity benefits of CR.

So while CR may not increase BAT or BAT-thermogenesis per se, so it doesn't belong on the list I've compiled of BAT-inducers, it does seem to preserve BAT thermogenic capacity despite the high metabolic cost, at least when CRed rodents are kept in cold conditions. This last qualifier is particularly important for humans since we have much less BAT than rodents. In particular, if we humans want to prevent our body from eliminating all its BAT during CR, and I don't think it is too much of a stretch given the evidence to say, if we want to benefit from CR at all, some combination of practices to promote BAT is likely to be necessary. You can take you pick from the list I've compiled in this post, but cold exposure is by far the most effective intervention for promoting BAT.

--Dean

-----------

[1] Am J Physiol. 1987 Feb;252(2 Pt 1):E237-43.

Effect of warm or cold exposure on GDP binding and uncoupling protein in rat

brown fat.

Trayhurn P, Ashwell M, Jennings G, Richard D, Stirling DM.

The effects of acute and chronic exposure to different environmental temperatures

on the total tissue cytochrome oxidase activity, level of mitochondrial GDP

binding, and specific mitochondrial concentration of uncoupling protein have been

investigated in rat brown adipose tissue, a radioimmunoassay being used to

measure uncoupling protein. Acclimation at different temperatures for 3 wk

produced parallel changes in GDP binding, the concentration of uncoupling

protein, and the activity of cytochrome oxidase, each parameter rising with

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By now we are all quite familiar with the somewhat disappointing results in the CR monkey studies, particularly the failure 30% CR to extend the lifespan relative to non-obese controls in the NIA monkey cohort.

We saw in this study (PMID 25362635; discussed here), BAT-thermogenesis (resulting from cold exposure) may be necessary for the CR longevity benefits observed in rodents. Could the same be the case in monkeys? In other words, could the failure of CR to extend monkey lifespan have resulted from a failure to combine CR with cold exposure? It looks like a definite possibility.

From the full text of study [1], which specifies the details of the NIA monkey housing conditions:

The vivaria [where monkeys were housed] provided artificial lighting, maintained on a 12–12 LD cycle with lights on at 06:00. Room temperature (22–28 °C) and humidity (50–60%) were under automatic control.

So the ambient temperature of the NIA monkey environment ranged from 72 to 82 °F during the course of each day, which is on average is a little higher than thermal neutrality for rhesus monkeys, which appears to be around 75 °F [2]. This is also a lot higher than the constant 72 °F which is typical for CR rodent experiments, despite the fact that the thermal neutrality is higher for rodents than monkeys (and people).

Interestingly [1] also points out that after a while the CR monkeys didn't eat all that much, and weren't very motivated by food. This suggests to me they acclimated to their balmy housing conditions, and without the need for thermogenesis to keep warm, they downregulated their calorie needs. As a result, they ate less, but didn't live any longer...

So just like the study that showed CR didn't work when rodents were housed at or above thermally neutral conditions (PMID 25362635), the NIA monkey study showed CR didn't work in monkeys when there were housed at thermally neutral conditions. Unfortunately there wasn't (and likely never will be) a study of lifelong CR in monkeys housed in cool conditions...

But even without the "smoking gun" showing that CR+cold exposure extends lifespan in monkeys, the failure of CR to extend monkey lifespan under thermally neutral conditions seems like more suggestive evidence that if CR is to have a hope of working in humans it likely needs to be combined with cold exposure...

--Dean

----------

[1] Neurobiol Aging. 2005 Jul;26(7):1117-27. Epub 2004 Dec 10.

Age-related decline in caloric intake and motivation for food in rhesus monkeys.

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I am wondering what effect exercising in the cold has? I don't like the idea of subjecting myself to cold, just because it's uncomfortable, yet there have been many times in my life where I've gone for long runs in -30'C, or have run in 0'C in shorts and a t-shirt. I find this to not only be tolerable, yet enjoyable. This is some irony that since starting CR I often do find myself cold, and just suck it up and live with it.

I feel that there is something that occurs when exercising under cold conditions that leads to a mild-moderate euphoric feeling. I'm not sure if it's the release of dopamine, norepinephrine, or something else? Dr. Rhonda Patrick recently touched it in on her podcast on cryotherapy. (Her podcast is called Found My Fitness, and the one on cryotherapy is most recent in the list).

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I'll address your question about exercise, cold & BAT in my next post, since that is a pretty big topic. In researching it, I came across this study [1], which adds one more intervention to the list of BAT-activity inducers - fasting.

The researchers in [1] first screened 10 healthy young men for BAT using the standard labelled PET imaging method. They found 6 out of 10 of them had detectable amounts of BAT when exposed to mild cold conditions (62.5 °F for 2 hours). In those six, the standard measure of BAT activity was twice as high in response to mild cold exposure when they were in a fasted state relative to the postprandial state (i.e. after eating "a chicken–bacon sandwich and 200 mL of whole milk (545 kcal)"). Two important things to note about this results though. First, the subjects (obviously) had to have BAT to begin with for fasting to increase its activity. This doesn't doesn't provide evidence one way or the other about whether fasting actual causes the body to make more BAT. Second, the greater increase in BAT activity when fasting relative to after eating was predicated on cold exposure to induce BAT activity in the first place. Simply fasting in warm conditions is unlikely to promote much if any BAT activity.

While it is a bit controversial, fasting is yet another BAT-inducing intervention that has long been thought by many to promote health and possibly longevity. The link between fasting and elevated BAT activity is yet more evidence suggesting BAT may play an important causal role in manifesting the benefits of many health-promoting practices & interventions.

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:

The role of brown adipose tissue (BAT) in adult metabolism is poorly understood.This study aimed to examine the differential effects of an overnight fast and thepostprandial state on BAT activity.METHODS: We included 10 healthy, lean malevolunteers. BAT uptake of glucose was visualized using (18)F-FDG PET/CT duringmild cold exposure. Each subject underwent PET/CT twice. The first scan wasobtained after an overnight fast; the second after a standardized meal.RESULTS: (18)F-FDG uptake in BAT was observed in 6 of 10 volunteers. Thesesubjects were found to have a higher maximal standardized uptake value whenfasting (median, 13.1 g/mL; range, 6.1-27.6 g/mL) than when in the postprandialstate (median, 6.8 g/mL; range, 2.1-13.4 g/mL) (P = 0.03).CONCLUSION: Cold-stimulated (18)F-FDG uptake by BAT in humans is more pronouncedduring fasting. The lower maximal standardized uptake value in the postprandialstate may be explained by increased insulin-stimulated glucose uptake in muscle.

PMID: 22851631

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Back to your question about exercising in the cold. First, since I engage in nearly continuous, low-intensity exercise during the day, most of my cold exposure is paired with mild exercise. I too find cold to be much more tolerable (bordering on pleasant) when I'm active vs. sedentary. Whether exercising during cold exposure will attenuate or potentiate BAT creation/activation is not entirely clear. As discussed in this post, this study (PMID 24506871) found that endurance exercise results in the 'browning' of white adipose tissue, but via a different pathway than cold exposure (Irisin vs. FGF21). Here is the graphical abstract from PMID 24506871 showing the two different pathways:

But in contrast, this study [1], found that endurance trained young male athletes had lower BAT activity in response to cold exposure than lean, sedentary young men. It also found that while the precursor to Irisin (FNDC5) was elevated in athletes, Irisin itself was no different between the athletes and the couch potatoes, in apparent contradiction to the study above which found exercise increased Irisin which in turn converted WAT to BAT. So it appears the jury is still out on whether exercise really does increase BAT.

Regarding the effects of exercising in the cold on mood and the feeling of 'euphoria'. Obviously exercise is well documented to improve mood through release of the neurotransmitters serotonin, dopamine and endorphins. In contrast, the neurotransmitter norepinephrine (NE - also called noradrenalin) is the signalling molecule the brain & sympathetic nervous system uses to increase BAT activity in response to cold. I didn't know this, but low NE is also implicated in mood disorders & depression [2]. Interestingly, cocaine is a NE reuptake inhibitor, although it's thought to have its main impact via dopamine. Interestingly, sometimes people suffering from depression who don't respond to serotonin reuptake inhibitors are prescribed norepinephrine reuptake inhibitors to treat their depression.

So in short it is definitely conceivable that the combination of exercise and cold exposure could have additive positive psychological effects due to the different mood-boosting neurotransmitters they influence.

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Ok, I promise this will be my past BAT-related post for the day - but don't worry I've got a couple more in the pipeline for tomorrow :-)

In my continuing quest to discover new methods for stimulating BAT synthesis / activation, I came across new candidates in the full text of [1], which contained this diagram:

As you can see at the top of the diagram both cold exposure and "food ingredients" signal the sympathetic nervous system via a family of "transient receptor potential" channels ((TRPs) to release norepinephrine which activates white, beige and brown adipose cells to burn fat. The discussion in [1] of the "food ingredients" that activate TRPs is the following:

Actually, there are various ingredients in food acting as agonists for these TRPs [2], a representative of which is menthol, a cooling and flavor compound in mint, acting on TRPM8. TRPA1 is activated by allyl- and benzyl-isothiocyanates, pungent elements in mustard and Wasabi (Japanese horseradish). Among the TRP agonists, the most extensively studied is capsaicin, a pungent principle of chili pepper, which is a potent agonist for TRPV1.

So methol/mint, mustard & horseradish can be added to capsaicin/chilli and curcumin/turmeric as food ingredients that trigger BAT activity (although again, not necessarily new BAT synthesis). And tracking down reference [2], I found a couple more. Here are excerpts from the full text of [2] :

TRPV3 [another member of the TRP family] can alternatively be activated by camphor (92), irritant extracts from oregano and cloves (161)...

TRPM8 [another member of the TRP family] as an ion channel that could be activated by either menthol or cool temperatures....

Support for a functional role of TRPA1 [another member of the TRP family] in nociceptive neurons has come from the demonstration that pungent chemical ligands, including isothiocyanates such as those found in mustard oil, wasabi, and garlic, as well as other irritant chemicals such as acrolein, are capable of activating this channel (6, 9, 69).

I'd never heard of acrolein before, so I looked it up. It turns out it's present in a number of foods that many of us consider healthy, along with some unhealthy ones as well. From this CDC document:

All these new foods would greatly expand my list of BAT inducers, even if we eliminate the fried potatoes & animal products due to their other health downsides. So I'm going to do some consolidation to the list.

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:

This list of BAT inducers is looking more and more like a "who's who" list of the best known foods & lifestyle choices for health and longevity. It's pretty amazing, and perhaps not coincidental, that they all have been shown to increase BAT activity...

Activation of brown adipose tissue (BAT) controls energy homeostasis in rodents and humans and has emerged as an innovative strategy for the treatment of obesity and type 2 diabetes mellitus. Here we show that ageing- and obesity-associated dysfunction of brown fat coincides with global microRNA downregulation due to reduced expression of the microRNA-processing node Dicer1. Consequently, heterozygosity of Dicer1 in BAT aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose metabolism. Analyses of differential microRNA expression during preadipocyte commitment and mouse models of progeria, longevity and DIO identified miR-328 as a regulator of BAT differentiation. Reducing miR-328 blocked preadipocyte commitment, whereas miR-328 overexpression instigated BAT differentiation and impaired muscle progenitor commitment-partly through silencing of the β-secretase Bace1. Loss of Bace1 enhanced brown preadipocyte specification in vitro and was overexpressed in BAT of obese and progeroid mice. In vivo Bace1 inhibition delayed DIO-induced weight gain and improved glucose tolerance and insulin sensitivity. These experiments reveal Dicer1-miR-328-Bace1 signalling as a determinant of BAT function, and highlight the potential of Bace1 inhibition as a therapeutic approach to improve not only neurodegenerative diseases but also ageing- and obesity-associated impairments of BAT function.

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Dean - thanks for taking the time to look into this. It's funny how the same thing (increasing BAT) can be accomplished via so many different foods/mechanisms. I also believe it's no coincidence that some of these foods that do us well through other mechanisms also apparently have a BAT mechanism too. It's a little ironic that chilli peppers contribute to BAT, though they make me sweat so much!

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One of the reasons chilli peppers make you sweat is that they induce thermogenesis in BAT, causing your actually be hotter. Your body sweats to compensate. Dr. Greger has a video (embedded below) on how to boost brown fat thermogenesis besides cold exposure. In it, he talks about a study [1] which found hot peppers increase metabolic rate, but only in people with measureable brown fat. Here is the figure showing the differential response of resting energy expenditure in BAT-positive and BAT-negative men, during the two hours after ingestion of either capsaicin or a placebo while hanging out in warm conditions (81 °F):

The capsaicin raised metabolic rate by about 120kcal/day, but only in the group of men who had measurable BAT. So it definitely looks like part of the 'burn' (bern? :-)) you feel as a result of eating chilli peppers is literally more heat generated by BAT. Interestingly, in another paper by these same researchers [2], they found that after six weeks of daily ingestion of capsaicin the group who initially had no measurable BAT displayed "a slight but significant increase in cold-induced thermogenesis – an index of BAT activity – in individuals given capsinoids daily for 6 weeks."

So hot peppers may not only activate existing BAT, but also chronic ingestion of capsaicin may (slightly) increase the amount of BAT you have.

--Dean

P.S. For anyone who wants a quick primer on BAT in humans, Dr. Greger has a good introductory video:

PURPOSE OF REVIEW: Capsaicin and its nonpungent analog (capsinoids) are known tobe food ingredients that increase energy expenditure and decrease body fat. Thisarticle reviews the role of brown adipose tissue (BAT) for the thermogenic effectof these compounds in humans and proposes the possibility of some otherantiobesity food ingredients.RECENT FINDINGS: A single oral ingestion of capsinoids increases energyexpenditure in human individuals with metabolically active BAT, but not thosewithout it, indicating that capsinoids activate BAT and thereby increase energyexpenditure. This finding gave a rational explanation for discrepant results ofthe effects of capsinoids in the previous studies. Human BAT may be largelycomposed of inducible 'beige' adipocytes more than typical brown adipocytesbecause its gene expression patterns are similar to beige cells isolated frommurine white fat depots. In fact, preadipocytes isolated from supraclavicular fatdeposits - where BAT is often detected - are capable of differentiating intobrown-like adipocytes in vitro, providing evidence of inducible brownadipogenesis in adult humans.SUMMARY: As human BAT may be inducible, a prolonged ingestion of capsinoids wouldrecruit active BAT and thereby increase energy expenditure and decrease body fat.In addition to capsinoids, there are numerous food ingredients that are expectedto activate BAT and so be useful for the prevention of obesity in daily life.

PMID: 23298960

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[2] The FASEB Journal. 2012;26:252.4

Activation of brown adipose tissue by acute and chronic administrations of capsinoids in humans

1 Laboratory of Histology and Cytology, Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan

2 Department of Nutrition, School of Nursing and Nutrition, Tenshi College, Sapporo, Japan

Objective: Capsinoids, nonpungent capsaicin-related substances, are known to increase brown adipose tissue (BAT) thermogenesis and whole-body energy expenditure (EE), and reduce body fat in small rodents. The objective of this study was to clarify whether BAT is involved in the thermogenic effects of capsinoids in humans.

Results: Eighteen male volunteers underwent fluorodeoxyglucose- positron emission tomography after 2-h cold exposure at 19 °C, and were divided into BAT-positive and - negative groups. Thermogenic responses to orally ingested capsinoids (9mg) or placebo were examined by indirect calorimetry at 27 °C. Thermogenic responses to cold at 19 °C (CIT) were also examined before and after daily ingestion of capsinoids for 6 weeks.

Results: Oral ingestion of capsinoids increased EE in 1 h by 15.2 ± 2.6 kJ/h in the BAT-positive group, more than in the BAT-negative group (1.7 ± 3.8 kJ/h). Placebo ingestion produced no significant change in either group. CIT in the BAT-negative group was much lower than that in the BAT-positive group, but it increased after 6-week capsinoids ingestion.

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Here is another one for the list - foods rich in the amino acid L-arginine. This review [1], cites a number of studies in which supplementing the diet of rodents with L-arginine increased BAT. One good one is [2], which had four groups of mice, fed either a normal diet with or without extra arginine or obesity-inducing high-fat diet with or without extra arginine. At the end of 15 weeks, both arginine groups has about 35% more BAT than their respective control groups, and had gained less weight despite eating identical amounts of food!

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In this post discussing PMID 3668686, it's clear that a diet that is overall low in protein promotes BAT. Here is another study [1] showing even more directly that a low-protein diet stimulates BAT activity and energy expenditure. In my last post, I pointed to evidence that the amino acid arginine appear to boost the amount of brown fat activity. But what about the mother of all protein-related, longevity-promoting dietary interventions - methionine restriction (MR)? Could the benefits of MR have something to do with BAT? Let's find out...

The two most cited studies documenting the longevity benefits of MR are this study [2] of rats and this study [3] of mice. Below are the survival curves of MR rats (left) and mice (right) from the two studies:

In rats, MR resulted in an mean lifespan extension of 20%, and a maximum lifespan extension of 12%. In fact, MR is one of the very few interventions that has ever been shown to increase max-lifespan. A fact I didn't know is that the MR rats ate more calories (after normalizing for body weight), but weighed less, than controls. Here is the body weight (left), absolute food intake (middle) and BW-normalized food intake (right) for MR rats (triangles) vs. control rats (circles).

As you can see, the MR rats gained no weight, and weighed significantly less than the control rats, despite eating nearly as much absolutely, and significantly more than controls once adjusted for body weight. The mice in [3] were similar in this regard to the rats in [2]. Namely:

Mice given the control diet consumed an average of 3.8 ± 0.7 g day−1 (mean ± SD), as compared with 4.3 ± 1.1 g day−1 for mice receiving the [methionine-] restricted diet. These data provide no evidence for the idea that the low-methionine food is less palatable than the control diet. ... the data are consistent with previous reports, from rat studies, that animals on the low-methionine diet consume at least as much food per gram body weight as controls.

Despite consuming more food, the MR mice in [3] also weighed significantly less than controls as you can see from this diagram:

Hmmm.... increased food consumption without weight gain, resulting in increased longevity. You should know by now where this is headed...

Yup - you guessed it. Methionine restriction is yet one more way to increase BAT, as evidenced by [4] and [5]. Focusing on [5], researchers studied MR rats vs. controls. Again the MR rats ate more for their size, but weighed less than controls. The MR rats were not thinner because of increased voluntary activity:

[There was] no evidence that the higher [energy expenditure] in MR rats was attributable to increased voluntary activity at night. In addition, ambulatory activity of the MR group during the day was significantly lower than that of the control group.

But the MR mice did have a higher core body temperature (by about 2°F!) which explains their increased energy expenditure and their low weight despite eating more. And the cause of this increase in core body temperature in the MR rats? Increased BAT activity, as is evidenced by this graph of uncoupling protein-1 expression in BAT, a marker for BAT thermogenic activity :

In support of UCP1's importance in the metabolic impact of MR, study [7] of mice lacking UCP1 found:

Interestingly, MR appears to 'work its magic' through increased expression of FGF21 [6]. This is interesting, because in this post we saw that mice genetically engineered to overexpress FGF21 ate more, weighed less, and live longer than control mice, just like the MR mice. And we've also seen cold exposure elevates FGF21 in rodents and people (PMID: 23150685). So it appears MR and cold exposure have similar influences on the body, and both act through upregulation of FGF21.

In summary, a (perhaps the) major physiological change resulting from methionine restriction is an increase in BAT activity via UCP1, which results in higher energy expenditure & food intake, but no increase in body weight. And of course, we know that methionine restriction results in increased lifespan. The evidence that methionine restriction promotes health and longevity via increased BAT activity would seem to put to rest any lingering doubts anyone might still harbor about the potential benefits of BAT and cold exposure.

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:

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In this and the following two posts, I'm going to further explore some pretty compelling (although circumstantial) evidence in favor of my hypothesis that increasing brown fat, and increasing energy expenditure via UCP-mediated thermogenesis (via cold exposure or other means), improves health & longevity by looking at three long-lived rodents species, the grey squirrel, the naked mole rat, and bats. The latter two are well known to have extended longevity, but not until I started looking into it did I realize the cute little guy in the tree outside my house is a member of a 'longevity superstar' species.

I'll start with him, since he's much more analogous to the typical rodents (mice & rats) used in longevity experiments. I'm referring to the Eastern Grey Squirrel (or GS for short) otherwise known by it's scientific name, Sciurus carolinensis. For those of you who aren't familiar with them, here is what they look like:

Cute little guys, aren't they?!

As I alluded to, GSs are extraordinarily long-lived relative to other terrestrial rodents [Note: I'll deal with flying rodents (bats) and subterranean rodents (nake mole rates) in my next two posts]. Here is a table of lifespans of various common small terrestrial rodents (adapted from [1]):

As you can see, the GS lives about 6x as long as (non-mutant) mice and rats. For anyone living in the northern latitudes of North America, you know that GSs get a lot of cold exposure. They don't hibernate in winter, but can often be seen like the one above, scurrying around happily in the snow even in the coldest of winter conditions. From [2], "Active grey squirrels have been observed at -30 °C (-22 °F) under a 30 km/h wind." Nevertheless, as you can see from the table, their mean core body temperature is higher (by about 3 °F!) than mice or rats.

So how do they manage to maintain such a high body temperature in cold conditions, and how (probably) do they live so long? You guessed it - via thermogenesis, much of it non-shivering thermogenesis (NST) mediated by BAT.

In [2], researchers kept 65 grey squirrels for several years in individual (2'x2'x4') cages at either warm (25°C = 77°F) or cold (1°C = 34°F!) temperatures. The GSs were fed the following natural diet (which is surprisingly similar to my own diet) :

Weekly diet consisted of 300-400 g of shelled nuts (walnuts, filberts, almonds, and peanuts in a 2:2:2:1 mixture) supplemented with an apple and either a carrot, a corncob, or a few mushrooms.

Holy cow - take a look at that again. Do you realize how many nuts that is? These GSs were eating about 50g of shelled nuts per day, which is almost 10% of their body weight. The human equivalent would be to eat about 15 lbs (7 kg) of shelled nuts per day. Ignoring the other food items, the nuts alone provide the squirrels with the human-equivalent of 38,000 kcal/day! I thought I ate a lot :-).

Lets assume the GSs ate 50g of nuts, and got the calorie-equivalent of another 10g of nuts from the other foods in their diet per day. That would be ~60g of nuts / day. At 5.5 kcal/g of nuts that equals 330kcal / day. Since adult GSs weigh about 500g, that would be the equivalent of 660 kcal / kg-BW-per-day.

From a human perspective, 660 kcal / kg of body weight per day seems like an awful lot. But how does this compare with other rodents, particular their close-ish (sized) cousin - the rat? From the post immediately preceding this one, consider this diagram of weight and food intake for laboratory rats. Ignore the meth-restricted rats and focus on the control rats eating a normal, ad-lib diet (open circles):

As you can see, the normal fed rats were eating about 15g of food per day. From the Purina rodent chow website, typical lab rat food has 4.09 kcal/g. So that is 61kcal / day. Normalizing for their ~300g average body weight (from left diagram), that means the lab rats were eating ~200 kcal / kg-BW-per-day.

So the caged grey squirrels were naturally eating over 3x as many calories as the ad-lib fed control rats in the meth-restriction study, even after normalizing for body weight. This isn't too surprising given that the GSs were housed at 34°F, and hence had to generate a lot of heat to maintain their body temperature relative to the rats who were housed at a relatively balmy, but still below thermal neutrality, 72°F in the meth-restriction study. In particular, from the full text of [2]:

During cold exposure, winter-acclimatized gray squirrels are capable of a peak metabolic rate 13.5 times their predicted standard metabolic rate (SMR). Some 20%-25% of the cold-induced heat production is due to nonshivering thermogenesis (NST). The remainder is attributed to shivering and indicates a capacity to reach a metabolic rate 10 times the predicted SMR by shivering This performance ranks among the highest reported for homeothermic animals. In contrast to shivering, NST is subjected to seasonal variation in the gray squirrel. The maximum noradrenaline-invoked [bAT-mediated] thermogenesis is 3.2-3.5 times greater in cold-acclimatized than in warm-acclimatized animals.

The paradoxical "black" grey squirrel (yup - they come in black too), which are found in more northern regions than the greys, has an even higher capacity for NST than the greys.

In short, grey squirrels are champions at cold acclimation and develop large BAT deposits in response to cold exposure. They eat a ton of calories, but stay slim by burning them off through both shivering and non-shivering thermogenesis. And they live an extraordinary long time, 6x as long as their similarly-sized cousins, rats.

While this case study of grey squirrels doesn't prove that eating lots of calories and burning them off via thermogenesis causes increased lifespan, but it is one more piece of very suggestive, circumstantial evidence. In my next posts, we'll look at naked mole rats and bats...

During cold exposure, winter-acclimatized gray squirrels are capable of a peak metabolic rate 13.5 times their predicted standard metabolic rate (SMR). Some 20%-25% of the cold-induced heat production is due to nonshivering thermogenesis (NST). The remainder is attributed to shivering and indicates a capacity to reach a metabolic rate 10 times the predicted SMR by shivering This performance ranks among the highest reported for homeothermic animals. In contrast to shivering, NST is subjected to seasonal variation in the gray squirrel. The maximum noradrenaline-invoked thermogenesis is 3.2-3.5 times greater in cold-acclimatized than in warm-acclimatized animals. This is primarily interpreted as a means to extend the thermal zone over which muscles can be freely allocated to activities other than shivering While the heat production induced by cold is independent of color morph in warm-acclimatized squirrels, black individuals have a greater NST capacity (by 11%) and a lesser rate of estimated heat loss in the cold (by 18% at -10° C) than gray ones. These results are consistent with the reported predominance of melanistic morphs in the northern part of the species' distribution.

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Thanks for all the great info Dean. Its funny to me how so many people talk about CR mimetics when CR itself might just be a BAT mimetic. It seems that many hard core CRONies focus on keeping glucose low and stable. From what I've been reading about BAT activation, that is one of the major health promoting benefits. Here is one paper related to this:

"These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans and support the notion that BAT may function as an anti-diabetic tissue in humans."

So the "real" scientific studies are out there. But what's a man to do who wants to apply this to his own life? I must say, I find the "cool fat burner" guy hilarious (and goofy), but also inspirational. That guy has done quite a lot of personal experimentation and has created many interesting videos. His personal experiments are not scientifically rigorous, however many studies published in reputable peer reviewed journals seem to back up the things that he reports. Anyway, in one of his videos he mentions binging on junkfood including multiple slices of pie plus 18 scoops of ice cream (!) to demonstrate the impact of BAT activation on blood glucose - 1.5 hours after this binge, his blood glucose was only 90, and his fasting number the next morning was 66! I immediately thought that if this were true, it could become a serious health intervention and may even change the way us "longevists" do things.

So anyway, I have been wanting to try this out on myself to see how my own body reacts. I have been trying to build my BAT and activate it daily now for a few weeks and I feel like I have made quite a bit of progress in a short amount of time. Interestingly, I do many if not most of the things from Dean's list of things that activate/build BAT including CR, fasting, low protein (plant based) diet, and I regularly eat almost all of the foods known to activate BAT, so I should be a prime candidate for this stuff.

I wasn't going to eat two slices of pie and 18 scoops of ice cream, but as circumstances would have it, I ended up at a "Friendly's" on Sunday with my family (apparently they have not all shut down yet, haha). I'm not recommending this to anyone else, but I sacrificed myself for science so you guys wouldn't have to, and ate one of their Veggie burgers first, followed by one one of these:

Reese's Pieces Sundae Calories:930

Fat Calories:480

Total Fat (g):53

Saturated Fat (g):26

Cholesterol (mg):90

Sodium (mg):360

Total Carbohydrates (g):95

Sugars (g):67

The veggie burger stats:

Total Calories:561

Fat Calories:244

Total Fat (g):27

Saturated Fat (g):6

Cholesterol (mg):10

Sodium (mg):834

Total Carbohydrates (g):66

Sugars (g):10

Dietary Fiber (g):5

Protein (g):13

I went straight home after that and wore the techkewl vest for 3 hours (no exercise) then tested my blood glucose. It was 76. The next morning reading was 79. I would say those readings are pretty good considering the circumstances. Would have been better to do this with a control first, and take a closer post prandial measurement. Maybe next time

I'd be interested in other people's self experimentation results...

-Gordo

Edited March 16, 2016 by Gordo

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Great experiment Gordo - thanks for sharing. That looks like a tasty sundae!

I'm wondering if you've seen a change in your resting heart rate as a result of cold exposure and BAT activation? Mine seems to have gone up pretty substantially. My Fitbit reports that over the last several months, since I began my cold exposure experiments in earnest, my resting HR has gone from 42-45 BPM to 53-56 BPM. One of the well-known metabolic effects of the elevated norepinephrine that accompanies cold exposure is an elevated heart rate. Have you observed anything similar in your HR?

P.S. It's still cold here in Pennsylvania, but I went ahead and ordered a Cool Fat Burner system. I went for the whole 9-yards, getting their $157.99 deluxe combo pack, which ends up being $185 with tax & shipping. I'll report back once I receive and test it.

--Dean

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In my first post in this three rodent series, I discussed how the hardy, outdoorsy grey squirrel has a lot of BAT (especially in winter), burns a lot of calories via thermogenesis, and lives an extraordinarily long time - 24 years.

But what about the rodent longevity champion - the tiny naked mole rat (NMR), scientific name Heterocephalus glaber? They weigh on 35g (a little over an oz, and less than a 1/10th of a rat or squirrel) and live up to a truly remarkable 32 years the longest of any rodent. They aren't nearly as cute as grey squirrels though...

How's that for an understatement?! They've got a face (sort of) that only a mother could love :-).

Also, unlike grey squirrels and almost all other mammals, NMRs are poikilotherms (rather than homeotherms), meaning their body temperature varies considerably with ambient temperature Ta. They spend their entire life underground in quite warm (31°C = 88°F) constant-temperature (daily deviation less than ±1-2°C) burrows in equatorial East Africa. In such constant, balmy conditions, and since they allow their body temperature to vary anyway, you'd think they'd have no trouble with regulating their body temperature and hence not have any need for BAT or thermogenesis - right?

But then again - look at them. They're called naked mole rats for a reason - they have no coat to keep them warm like most other mammals do. Plus, their relatively balmy 31°C burrows are still considerably cooler than the 36-38°C body temperature that most rodents maintain.

So which is it? Do they or don't they have much BAT and generate much heat through BAT-thermogenesis? If they don't, doesn't that shoot down (or at least cast doubt on) my theory that BAT and BAT-thermogenesis are key for longevity?

Reading the abstract, study [1] at first seem pretty damning for my theory. In it, the researchers split 15 NMRs into two groups, one housed at normal burrow temperature (31°C) and the other kept at a temperature that is quite chilly for NMRs (25°C) for over a year. Then they compared the two groups' non-shivering (BAT) thermogenic response to an injection of noradrenaline to simulate cold exposure. Here are the graphs of the results. The cold acclimated NMRs are the hashed bars, and the control NMRs are the open bars:

What's shown is metabolic rate (left) and body temperature (right) of the two groups of NMRs, at baseline (B), after an injection of saline (S), and after an injection of BAT-stimulating noradrenaline (NA). As you can see, the cold-acclimated NMRs had a slightly higher metabolic rate, and slightly higher body temperature, relative to control NMRs either at baseline and after saline injection. While these increases were statistically significant, they were relatively small; nothing to write home about. More to the point, notice that chronic cold exposure does not potentiate the NMRs thermogenic response. If anything, the cold-acclimated NMRs exhibited a slightly smaller increase in metabolic rate and body temperature in response to the NA injection than did controls.

So what gives? Why don't NMRs increase their ability to generate heat via BAT-mediated, non-shivering thermogenesis (NST) in response to chronic cold exposure like other rodents, mammals, and people do? The authors suggest that one possible explanation is that evolutionary pressure caused them to lose their ability to cold adapt, in a similar fashion to why/how they lost their hair and (most of) their eyesight:

Why does the naked mole-rat not increase its non-shivering thermogenic capacity in response to

chronic cold exposure? From an evolutionary perspective, one might argue that naked mole-rats

have lost the ability to increase the thermogenic capacity of their BAT, for they have exploited a

Zone] (31–34 °C; Buffenstein and Yahav, 1991) and have little need for cold-tolerance.

But hold on - does that mean they lack BAT and BAT-thermogenesis? Look at the graph on the left again. The metabolic rate of both groups of NMRs went up by ~350% as a result of the noradrenaline injection. The authors observe that this is a huge increase relative to other rodents:

[This] NST response is substantial, being in excess of a 350% increase in VO2 basal levels.

This is far in excess of that which is seen in laboratory rodents (e.g. Syrian hamster) that

resulted in a more than 120% increase in resting metabolism above basal levels [in NMRs].

And study [2] shows that NMRs do indeed have BAT that is sensitive to catecholamines like noradrenaline. So here is how the authors of [1] interpret their findings:

Relatively speaking then, the cold stress endured by the naked mole-rat at temperatures

even slightly below thermoneutrality is very high and the resulting increase in metabolism is

again indicative of the sustained high thermogenic capacity of their BAT. Because small changes in

Ta below thermoneutrality represent such a severe cold-stress for these mammals, their BAT may

already be maximally stimulated, and as such, thermogenic capacity would be at a maximum

with no further cold-induced increase possible.

In other words, due to their nakedness and other factors, naked mole rats are very sensitive to changes in ambient temperature. As a result, the authors suggest that simply by living in their natural habitat they have maxed out the amount of BAT they carry, and their BAT thermogenic capacity, which kicks in to help them generate heat in response to even small changes in ambient temperature. Their BAT is already topped off, so additional chronic cold exposure can't increase it any further.

So in a sense, naked mole rats are the exception that proves the rule. They are the exception because they don't increase BAT levels in response to chronic cold exposure like other rodents and people do. But they "prove the rule" (or more accurately, support my conjecture) that having lots of BAT and employing it to burn calories for heat to maintain body temperature in colder-than-normal conditions is health & longevity promoting. Naked mole rats appear to fit this rule very well, in that they have lots of very sensitive BAT that kicks in for small temperature deviations, and they living a very long time, relative to other rodents.

Note: The below is an addendum added a couple days later...

As the data from [1] showed, NMRs have an unusually large amount of very sensitive BAT. Study [3] points to a possible explanation. Here is a quote from [3]:

"Non-shivering thermogenesis is a major heat production process in mammals that mainly depends on the action of UCP1, one of the 39 vertebrate genes that changed uniquely in NMR [relative to other rodents and humans]...

Taken together, these observations indicate a tight association of UCP1 function with the unique thermoregulation in NMR [referencing [1] ]."

Interestingly, study [4] found that mutations in the various human UCP genes are also associated with human longevity, and study [5] found that UCP1 gene mutations in humans was specifically associated with variations in individual human longevity.

So there you go, more evidence that naked mole rats have uniquely-tuned, highly-sensitive brown adipose tissue as a result of mutations to their UCP1 gene, and this may at least in part explain their extraordinary longevity. And natural UCP gene mutations in people, including mutations to UCP1, also appear to impact human longevity.

Author information:(1)Department of Anatomical Sciences, University of the Witwatersrand,Johannesburg, South Africa.

The thermogenic potential of the interscapular brown fat pad in the nakedmole-rat Heterocephalus glaber, that exhibits poikilothermic thermal responses tochanging temperatures is reported. Histological and ultrastructural study of thebrown fat pad showed that it consists of layers of skeletal muscle interposedbetween the layers of brown adipose tissue with both unilocular and multilocularadipocytes. Large numbers of mitochondria were present between and around thelipid droplets of these cells. Glyoxylic acid condensation, used to demonstratecatecholaminergic nerves, was evident in low concentrations in the connectivetissue between the brown adipocytes. A 3-dimensional computer-aidedreconstruction of the fat pad showed the extent and ramification of nerves andblood vessels between the adipocytes. These findings show that although the nakedmole-rat is regarded as an endothermic poikilotherm, it possesses anatomicalfeatures usually found in homeothermic mammals, which are essential forthermogenesis.

PMCID: PMC1467613PMID: 9147219

-----------

[3] Nature. 2011 Oct 12;479(7372):223-7. doi: 10.1038/nature10533.

Genome sequencing reveals insights into physiology and longevity of the naked

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Hey Dean, yes, my resting heart rate is higher than before. I'll have to analyze my data to compare to pre-cold exposure readings. I am one of those people that for a long time thought a super low heart rate and metabolism were critical for longevity, but I have since changed my mind about this based on the observational science. There is no evidence that your heart for example "wears out" faster just because its had more "lifetime beats" compared to someone else. And a higher metabolism doesn't necessarily mean your body's cells are dividing faster, therefore resulting in shorter telomeres/accumulation of genetic damage, etc. Maybe that is the general "rule" but BAT burning up excess calories seems to be one exception to the rule. Although I'd love to see some more data confirming that.

FYI: When I was looking at the cool fat burner product page, at least the one I was looking at said it came with 1 kg of phase change material. The techkewl vest comes with 2.2 kg of PCM, so more than double. Just wanted to point that out. That said, I would like to design my own vest that better targets BAT, which I plan to do at some point. Lastly, I got the techkewl in "like new" condition from amazon warehouse for $85, and it looked brand new to me, so anyone interested in a little savings should check for that...

Edited March 2, 2016 by Gordo

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Over on the methionine restriction thread, Sirtuin posed some questions regarding cold exposure. I'm answering them here since this seems like the appropriate thread for such a discussion. So here goes.

What are your thoughts on cold exposure and cardiovascular / health risks?

A quick search on the title of that paper (PMID 23823482) would have shown Al Pater posed the same question, pointing to the same study, in this post. I addressed it in this post and again in this one. Bottom line - that study uses a very poor rodent model of atherosclerosis. A much better mouse model of CVD shows dramatic benefits of cold exposure, as do human studies. Here is a brand new review article [1] of both the animal and human research on brown fat and CVD, which concludes:

Yes - that isn't too surprising. Low temperatures put greater stress on the cardiovascular systems of people at risk for CVD. In fact, my dad died at age 69 shoveling snow. He was 60 lbs overweight, diabetic and had high blood pressure. He'd smoked 2 packs a day for 20 years, before quitting after a heart attack at age 55.

Your second link suggests something similar, referring to the

Most of them [deaths in winter] are due to strokes and heart attacks.

But correlation is not causation. Just because more people die of heart attacks and strokes in wintertime doesn't mean that cold exposure promotes the development of CVD. It appears just the opposite, as described above.

That's a funny one [2]. From the free full text, here is their scatter plot of thyroid cancer rate as a function of temperature for each of the 50 states:

First off, that doesn't look like a very strong correlation to me. Second, there are a lot of things that people living in warm southern states do that I could imagine influencing the risk of thyroid cancer, that have nothing to do with ambient temperature.

Finally, and most importantly, look at the Y-scale of the graph. Change in risk is going from 5 to 10 cases of thyroid cancer per 100,000 people. Thyroid cancer is in fact quite rare. Last year, just under 2000 people died in the US of thyroid cancer, according to the American Cancer Society. This compares with the over 600,000 people who die from cardiovascular disease in the US each year. Here is a graphic for comparison of those two risks.

So even if cold exposure did modestly increase thyroid cancer risk (which is questionable), it seems a small price to pay for decreased risk of our number one killer, cardiovascular disease.

In the summer, I appear much more vascular with warm hands, warm feet, a large network of thick arteries at the surface of my skin, etc. Yet, in the winter, I get cold hands, cold feet, cold ears, a cold nose, and my vascularity recedes (I otherwise find the cold quite comfortable, haha.) It's very difficult to draw blood for me in a cold lab. It seems like circulation is directly impaired here, and that this would not be an ideal stressor? I've tried various methods to acclimate to the cold and prevent these effects from occuring, but it's fairly automatic for me at a low level unless I dramatically increase calories + protein and aerobic activity to increase thermogenesis (eg. my cold shower post exercise.)

I wear gloves when exposing myself to cold to keep my hands from getting too cold. I have a pair with the fingertips cut off so I can type ☺

Regarding calories - if you read over this entire thread, perhaps you'll become a lot less convinced that restricting calories per se is particularly beneficial...

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Thanks for the confirming that you've seen an increase in your resting heart rate as well as result of cold exposure.

FYI: When I was looking at the cool fat burner product page, at least the one I was looking at said it came with 1 kg of phase change material. The techkewl vest comes with 2.2 kg of PCM, so more than double. Just wanted to point that out.

The Cool Fat Burner combo pack I bought is listed as weighing 3kg. Plus I plan to experiment with creating my own phase change cooling packs, as we discussed here. By the way, have you tried making your own cooling packs?

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Before my bat BAT post, just a quick addition to my naked mole rat (NMR) and BAT thermogenesis post (I've also edited the post above, but nobody following along in 'real time' would see it).

As the data from PMID 12443938 showed, NMRs have an unusually large amount of very sensitive BAT. Study [1] points to a possible cause. It found that:

"Non-shivering thermogenesis is a major heat production process in mammals that mainly depends on the action of UCP1, one of the 39 vertebrate genes that changed uniquely in NMR [relative to other rodents and humans]...

Taken together, these observations indicate a tight association of UCP1 function with the unique thermoregulation in NMR [referencing PMID 12443938 that I discussed above]."

Interestingly, study [2] found that mutations in the various human UCP genes are also associated with human longevity, and study [3] found that mutations to the UCP1 gene in humans was specifically associated with variations in individual human longevity.

So there you go, more evidence that naked mole rats have uniquely-tuned, highly-sensitive brown adipose tissue as a result of mutations to their UCP1 gene, and this may explain at least part of their extraordinary longevity. And natural UCP gene mutations in people, including mutations to UCP1, also appear to impact human longevity.

--Dean

-----------

[1] Nature. 2011 Oct 12;479(7372):223-7. doi: 10.1038/nature10533.

Genome sequencing reveals insights into physiology and longevity of the naked